8-azaprostaglandin carbonate and thiocarbonate analogs as therapeutic agents

ABSTRACT

The present invention provides a compound represented by the general formula I;                    
     wherein A, Ar, X, Z, n, x, y, R and R 3  are as defined in the specification.

RELATED APPLICATION

This patent application is a divisional of application Ser. No.10/453,818 now U.S. Pat. No. 6,734,201 filed Jun. 2, 2003 which ishereby incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to 8-Azaprostaglandin carbonate andthiocarbonate analogues as therapeutic agents, e.g. for the managementof glaucoma.

2. Description of Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives have been reported to possessocular hypotensive activity, and have been recommended for use inglaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

Prostaglandins were earlier regarded as potent ocular hypertensives,however, evidence accumulated in the last decade shows that someprostaglandins are highly effective ocular hypotensive agents, and areideally suited for the long-term medical management of glaucoma (see,for example, Bito, L. Z. Biological Protection with Prostaglandins,Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252;and Bito, L. Z., Applied Pharmacology in the Medical Treatment ofGlaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune &Stratton, 1984, pp. 477-505. Such prostaglandins include PGF_(2α),PGF_(1α), PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkylesters, e.g. 1-isopropyl ester, of such compounds.

Although the precise mechanism is not yet known experimental resultsindicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et.al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

The isopropyl ester of PGF_(2α) has been shown to have significantlygreater hypotensive potency than the parent compound, presumably as aresult of its more effective penetration through the cornea. In 1987,this compound was described as “the most potent ocular hypotensive agentever reported” [see, for example, Bito, L. Z., Arch. Ophthalinol. 105.1036 (1987), and Siebold et.al., Prodrug 5 3 (1989)].

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF2α and its prodrugs, e.g., its1-isopropyl ester, in humans. The clinical potentials of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma are greatly limited by these side effects.

In a series of co-pending United States patent applications assigned toAllergan, Inc. prostaglandin esters with increased ocular hypotensiveactivity accompanied with no or substantially reduced side-effects aredisclosed. The co-pending U.S. Ser. No. 596,430 (filed 10 Oct. 1990, nowU.S. Pat. No. 5,446,041), relates to certain 11-acyl-prostaglandins,such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and11-isovaleryl PGF_(2α). Intraocular pressure reducing 15-acylprostaglandins are disclosed in the co-pending application U.S. Ser. No.175,476 (filed 29 Dec. 1993). Similarly, 11,15- 9,15 and 9,11-diestersof prostaglandins, for example 11,15-pivaloyl PGF_(2α) are known to haveocular hypotensive activity. See the co-pending patent applications U.S.Ser. No. 385,645 (filed 7 Jul. 1989, now U.S. Pat. No. 4,994,274), Ser.No. 584,370 (filed 18 Sep. 1990, now U.S. Pat. No. 5,028,624) and Ser.No. 585,284 (filed 18 Sep. 1990, now U.S. Pat. No. 5,034,413). Thedisclosures of all of these patent applications are hereby expresslyincorporated by reference.

8-Azaprostaglandin analogs are disclosed in PCT Patent Applications WO01/46140 A1, WO 02/042268 A2, WO 02/24647 A1, WO 03/007941 A1, EP 1 121939 A2 and Japanese Patent 2001-233792.

SUMMARY OF THE INVENTION

The present invention provides therapeutic agents comprising a compoundof formula I

wherein a wavy line represents either the α configuration or the βconfiguration and a dotted line represents the presence or absence of adouble bond;

A represents a single bond or a cis double (alkene) bond or a triple(alkyne) bond;

X is CO₂R, CONR₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂ or

n is 0 or an integer of from 1 to 4;

x and y are 0 or 1, provided however when x is 1, y is 0 and when x is0,

y is 1;

Z is S or O;

R is H or R¹;

R¹ is C₁-C₅ lower alkyl or alkenyl;

Ar is selected from the group consisting of aryl or heteroaryl radicals,having from 4 to 10 carbon atoms, e.g. phenyl, thienyl, furanyl,pyridyl, benzothienyl, benzofuranyl, naphthyl, or substitutedderivatives of said aryl or heteroaryl radicals, wherein thesubstituents maybe selected from the group consisting of C₁-C₅ alkyl,halogen, CF₃, CN, NO₂, NR₂, CO₂R and OR and R³ is R, OR, CH₂OR or COR.

These compounds are useful for treating diseases and conditions whichare responsive to treatment with prostaglandin analogues, e.g. glaucoma;cardiovascular; e.g. acute myocardial infarction, vascular thrombosis,hypertension, pulmonary hypertension, ischemic heart disease, congestiveheart failure, and angina pectoris; pulmonary-respiratory;gastrointestinal; reproductive and allergic diseases; osteoporosis andshock.

In a further aspect, the present invention relates to an ophthalmicsolution comprising a therapeutically effective amount of a compound offormula (I), wherein the symbols have the above meanings, or apharmaceutically acceptable salt thereof, in admixture with a non-toxic,ophthalmically acceptable liquid vehicle, packaged in a containersuitable for metered application.

In a still further aspect, the present invention relates to apharmaceutical product, comprising

a container adapted to dispense its contents in a metered form; and

an ophthalmic solution therein, as hereinabove defined.

DESCRIPTION OF THE DRAWING FIGURE

FIGS. 1-5 show schematics for the preparation of the compounds of theinvention wherein the numbered compounds and intermediates correspond tothe numbered compounds and intermediates of the Examples.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to 8-Azaprostaglandin analogs which areuseful as ocular hypotensives or for treating other diseases andconditions which are responsive to treatment with prostaglandinanalogues. The compounds used in

accordance with the present invention are encompassed by the followingstructural formula I:

The preferred group of the compounds of the present invention includescompounds that have the following structural formula II.

wherein a triangle at position C-12 represents β orientation.

The more preferred group of compounds have the following structuralformula III

In the above formulae, the substituents and symbols are as hereinabovedefined.

In the above formulae:

Preferably X is CO₂R and more preferably R is H or CH₃

Preferably n is 0 or 1 and Ar is phenyl or

n is 3 and x is 0

Preferably R³ is H

The above compounds of the present invention may be prepared by methodsthat are known in the art or according to the working examples below.The compounds, below, are especially preferred representative, of thecompounds of the present invention.

7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid methyl ester

7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid

(Z)-7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid methyl ester

(Z)-7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid

7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoicacid methyl ester

7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoicacid

7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid methyl ester

7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid

(Z)-7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid methyl ester

(Z)-7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid

7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoicacid methyl ester

7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoicacid

7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-hept-5-ynoicacid methyl ester

7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-hept-5-ynoicacid

(Z)-7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-hept-5-enoicacid methyl ester

(Z)-7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-hept-5-enoicacid

7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-heptanoic acidmethyl ester

7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-heptanoic acid

7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid methyl ester

7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid

(Z)-7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid methyl ester

(Z)-7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid

7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoic acidmethyl ester

7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoic acid

Pharmaceutical compositions including said compounds may be prepared bycombining a therapeutically effective amount of at least one compoundaccording to the present invention, or a pharmaceutically acceptableacid addition salt thereof, as an active ingredient, with conventionalophthalmically acceptable pharmaceutical excipients, and by preparationof unit dosage forms. The therapeutically efficient amount typically isbetween about 0.0001 and about 5% (w/v), preferably about 0.001 to about1.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate the application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

This invention is further illustrated by the following non-limitingExamples.

EXAMPLE 1

7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid methyl ester (5)

Step 1. Alkylation of Amide 1 to Give 3

Sodium hydride (60% dispersion in oil, 233 mg, 5.81 mmol) was added to asolution of amide 1 (1.33 g, 5.81 mmol) in DMF (10 mL). The reactionmixture was stirred at rt for 1 h, then iodide 2 (1.54 g, 5.81 mmol) wasadded as a solution in DMF (3 mL) via cannula. The reaction was heatedat 90° C. for 21 h then cooled to rt. Aqueous HCl (1.0 M, 50 mL) wasadded and the mixture was extracted with EtOAc (3×75 mL). The combinedorganic phase was washed with brine (3×50 mL), dried (Na₂SO₄), filteredand concentrated in vacuo. Purification of the residue by flash columnchromatography on silica (100% CH₂Cl₂→1% MeOH/CH₂Cl₂, gradient) afforded910 mg (43%) of 3.

Step 2. Deprotection of 3 to Give 4

HF-pyridine (4.0 mL) was added to a solution of silyl ether 3 (857 mg,2.33 mmol) in MeCN (8.0 mL) in a plastic scintillation vial. After 5 hat rt, the reaction was quenched with saturated aqueous NaHCO₃ (50 mL)and the mixture was extracted with EtOAc (3×50 mL). The combined organicphase was washed with brine (50 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica (100% CH₂Cl₂→2% MeOH/CH₂Cl₂, gradient) afforded570 mg (97%) of 4. Step 3. Thiocarbamoylation of 4 to give 5

Phenethyl isothiocyanate (70 μL, 0.47 mmol) and DABCO (66 mg, 0.59 mmol)were added to a solution of alcohol 4 (99 mg, 0.39 mmol) in THF (1.5mL). The reaction was heated at reflux for 6 h, then cooled to rt andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica (100% CH₂Cl₂→20% EtOAc/CH₂Cl₂→2% MeOH/CH₂Cl₂)afforded 22 mg (14%) of the title compound (5).

EXAMPLE 2

7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid (6)

Rabbit liver esterase (134 units/mg, 1 mg), ester 5 (6.0 mg, 0.015mmol), MeCN (0.1 mL) and pH 7.2 phosphate buffer (2.0 mL) were stirredtogether at rt overnight. MeCN (5.0 mL) was added and the reaction wasconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica (100% CH₂Cl₂→2% MeOH/CH₂Cl₂, gradient) afforded3.2 mg (55%) of the title compound (6).

EXAMPLE 3

(Z)-7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid methyl ester (8)

Step 1. Reduction of 4 to Give 7

Palladium on carbon (10 mol%, 5 mg) was added to a solution of alkyne 4(27 mg, 0.11 mmol) in MeOH (1.5 mL). The flask was evacuated andrefilled with hydrogen (3×), and the reaction mixture was stirredvigorously under a balloon of hydrogen for 1.3 h. The mixture was thenfiltered through celite, washing with MeOH (5 mL) and the filtrate wasconcentrated in vacuo to afford 26 mg (95%) of alkene 7.

Step 2. Thiocarbamoylation of 7 to Give 8

In accordance with Example 1, step 3, 7 (26 mg, 0.10 mmol) was convertedinto 35 mg (83%) of the title compound (8) after chromatography (100%CH₂Cl₂→60% EtOAc/CH₂Cl₂, gradient).

EXAMPLE 4

(Z)-7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid (9)

In accordance with Example 2, 8 (11 mg, 0.026 mmol) was converted into7.4 mg (70%) of the title compound (9).

EXAMPLE 5

7-(R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoicacid methyl ester (11)

Step 1. Reduction of 4 to Give 10

Palladium on carbon (10 mol %, 10 mg) was added to a solution of alkyne4 (47 mg, 0.19 mmol) in MeOH (1.5 mL). The flask was evacuated andrefilled with hydrogen (3×), and the reaction mixture was stirredvigorously under a balloon of hydrogen for 21 h. The mixture was thenfiltered through celite, washing with MeOH (5 mL) and the filtrate wasconcentrated in vacuo to afford 42 mg (88%) of alkane 10.

Step 2. Thiocarbamoylation of 10 to Give 11

In accordance with Example 1, step 3, 10 (19 mg, 0.074 mmol) wasconverted into 28 mg (90%) of the title compound (11) afterchromatography (100% CH₂Cl₂→50% EtOAc/CH₂Cl₂, gradient).

EXAMPLE 6

7-((R)-2-Oxo-5-phenethylthiocarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoicacid (12)

In accordance with Example 2, 11 (17 mg, 0.040 mmol) was converted into11 mg (67%) of the title compound (12).

EXAMPLE 7

7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid methyl ester (13)

A solution of 4 (52 mg, 0.21 mmol), DABCO (35 mg, 0.32 mmol) andphenethyl isocyanate (60 μL, 0.43 mmol) in THF (1.5 mL) was heated atreflux for 22.5 h. The reaction was cooled to rt then concentrated invacuo. Purification of the residue by flash column chromatography (100%CH₂Cl₂→50% EtOAc/CH₂Cl₂, gradient) afforded 86 mg (quant.) of the titlecompound (13).

EXAMPLE 8

7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid (14)

In accordance with Example 2, 13 (16 mg, 0.040 mmol) was converted into11 mg (72%) of the title compound (14).

EXAMPLE 9

(Z)-7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid methyl ester (15)

95% Ethanol (1.0 mL) was added to a slowly stirred mixture of nickel(II) chloride (86 mg, 0.66 mmol) and sodium borohydride (12 mg, 0.33mmol) under nitrogen. The mixture immediately turned black. After 15min, ethylenediamine (70 μL, 1.04 mmol) was added. After an additional15 min, a solution of alkyne 13 (53 mg, 0.13 mmol) in 95% ethanol (1.0mL) was added. The flask was evacuated and refilled with hydrogen (3×),and the reaction mixture was stirred vigorously under a balloon ofhydrogen for 22 h. The mixture was then filtered through celite, washingwith MeOH (5 mL) and the filtrate was concentrated in vacuo.Purification of the residue by flash column chromatography on silica(100% CH₂Cl₂→50% EtOAc/CH₂Cl₂, gradient) afforded 30 mg (56%) of thetitle compound (15).

EXAMPLE 10

(Z)-7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid (16)

In accordance with Example 2, 15 (17 mg, 0.042 mmol) was converted into12 mg (73%) of the title compound (16).

EXAMPLE 11

7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoicacid methyl ester (17)

A solution of 10 (22 mg, 0.085 mmol), DABCO (14 mg, 0.13 mmol) andphenethyl isocyanate (14 μL, 0.10 mmol) in THF (1.0 mL) was heated atreflux for 22.5 h. The reaction was cooled to rt then concentrated invacuo. Purification of the residue by flash column chromatography (100%CH₂Cl₂→50% EtOAc/CH₂Cl₂, gradient) afforded 34 mg (98%) of the titlecompound (17).

EXAMPLE 12

7-((R)-2-Oxo-5-phenethylcarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoicacid (18)

In accordance with Example 2, 17 (17 mg, 0.042 mmol) was converted into8 mg (48%) of the title compound (18).

EXAMPLE 13

7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-hept-5-ynoicacid methyl ester (19)

DABCO (51 mg, 0.45 mmol) and benzyl isocyanate (45 μL, 0.36 mmol) wereadded to a solution of 4 (76 mg, 0.30 mmol) in THF (2.0 mL). Thereaction was heated at reflux overnight. After 18 h, the reaction wascooled to rt and concentrated in vacuo. Purification of the residue byflash column chromatography (2 times: 1^(st) 100% CH₂Cl₂→2% MeOH/CH₂Cl₂,gradient and then 2^(nd) 10% EtOAc/CH₂Cl₂→50% EtOAc/CH₂Cl₂, gradient)afforded 105 mg (91%) of the title compound (19).

EXAMPLE 14

7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-hept-5-ynoicacid (20)

In accordance with Example 2, 19 (14 mg, 0.036 mmol) was converted into2 mg (15%) of the title compound (20) after chromatography (100%CH₂Cl₂→40% EtOAc/CH₂Cl₂→2% MeOH/CH₂Cl₂, gradient).

EXAMPLE 15

(Z)-7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-hept-5-enoicacid methyl ester (21)

In accordance with Example 9, 19 (82 mg, 0.21 mmol) was converted into71 mg (86%) of the title compound (21) after chromatography (10%→50%EtOAc/CH₂Cl₂).

EXAMPLE 16

(Z)-7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-hept-5-enoicacid (22)

In accordance with Example 2, 21 (18 mg, 0.046 mmol) was converted into17 mg (98%) of the title compound (22).

EXAMPLE 17

7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-heptanoic acidmethyl ester (23)

Palladium on carbon (10 mol %, 7 mg) was added to a solution of alkene21 (39 mg, 0.10 mmol) in MeOH (2.5 mL). The flask was evacuated andrefilled with hydrogen (3×), and the reaction mixture was stirredvigorously under a balloon of hydrogen for 3.5 h. The mixture was thenfiltered through celite, washing with MeOH (5 mL) and the filtrate wasconcentrated in vacuo to afford 33 mg (85%) of the title compound (23).

EXAMPLE 18

7-((R)-2-Benzylcarbamoyloxymethyl-5-oxo-pyrrolidin-1-yl)-heptanoic acid(24)

In accordance with Example 2, 23 (19 mg, 0.049 mmol) was converted into18 mg (98%) of the title compound (24).

EXAMPLE 19

7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid methyl ester (25)

DABCO (41 mg, 0.36 mmol) and pentyl isocyanate (37 μL, 0.28 mmol) wereadded to a solution of 4 (60 mg, 0.24 mmol) in THF (2.0 mL). Thereaction was heated at reflux overnight. After 21 h, the reaction wascooled to rt and concentrated in vacuo. Purification of the residue byflash column chromatography (100% CH₂Cl₂→50% EtOAc/CH₂Cl₂, gradient)afforded 82 mg (94%) of the title compound (25).

EXAMPLE 20

7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-ynoicacid (26)

In accordance with Example 2, 25 (9 mg, 0.025 mmol) was converted into 5mg (58%) of the title compound (26).

EXAMPLE 21

(Z)-7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid methyl ester (27)

In accordance with Example 9, 25 (54 mg, 0.15 mmol) was converted into48 mg (88%) of the title compound (27).

EXAMPLE 22

(Z)-7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-hept-5-enoicacid (28)

In accordance with Example 2, 27 (16 mg, 0.043 mmol) was converted into15 mg (98%) of the title compound (28).

EXAMPLE 23

7-(R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoic acidmethyl ester (29)

Palladium on carbon (10 mol %, 5 mg) was added to a solution of alkene27 (24 mg, 0.065 mmol) in MeOH (2.0 mL). The flask was evacuated andrefilled with hydrogen (3×), and the reaction mixture was stirredvigorously under a balloon of hydrogen for 5 h. The mixture was thenfiltered through celite, washing with MeOH (5 mL) and the filtrate wasconcentrated in vacuo to afford 24 mg (99%) of the title compound (29).

EXAMPLE 24

7-((R)-2-Oxo-5-pentylcarbamoyloxymethyl-pyrrolidin-1-yl)-heptanoic acid(30)

In accordance with Example 2, 29 (17 mg, 0.046 mmol) was converted into8 mg (49%) of the title compound (30).

The compounds of this invention are useful in lowering elevatedintraocular pressure in mammals, e.g. humans, and for treating otherdiseases and conditions which are responsive to treatment withprostaglandin analogues, e.g. glaucoma; cardiovascular; e.g. acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heart failure, andangina pectoris; pulmonary-respiratory; gastrointestinal; reproductiveand allergic diseases; osteoporosis and shock.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

What is claimed is:
 1. A method of treating ocular hypertension orglaucoma which comprises administering to an animal having ocularhypertension or glaucoma a therapeutically effective amount of acompound represented by the general formula I;

wherein a wavy line represents either the α configuration or the βconfiguration and a dotted line represents the presence or absence of adouble bond; A represents a single bond or a cis double (alkene) bond ora triple (alkyne) bond; X is CO₂R, CONR₂, CH₂OR, P(O)(OR)₂, CONRSO₂R,SONR₂ or

n is 0 or an integer of from 1 to 4; x and y are 0 or 1, providedhowever when x is 1, y is 0 and when x is 0, y is 1; Z is S or O; R is Hor R²; R¹ is H, R², phenyl, or COR²; R² is C₁-C₅ lower alkyl or alkenyl;Ar is selected from the group consisting of aryl or heteroaryl radicals,having from 4 to 10 carbon atoms, or substituted derivatives of saidaryl or heteroaryl radicals, wherein the substituents maybe selectedfrom the group consisting of C₁-C₅ alkyl, halogen, CF₃, CN, NO₂, NR₂,CO₂R and OR and R₃ is R, OR, CH₂OR or COR.